EP 0310745 B (FARMOS OY) Apr. 12, 1989 disclosed preparation of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole salt by two synthetic routes.
First synthetic route as starting material was used 2-acetyl-1-indanone, which was alkylated with ethylbromide in acetone in the presence of sodium carbonate to 2-acetyl-2-ethyl-1-indanone. The acetyl group was brominated with bromine in methanol and to imidazole by heating in formamide. Then the intermediate was hydrogenated in 2N hydrochloric acid in the presence of 10% palladium on carbon.
Second synthetic route disclosed in the same patent is following, as starting material was used 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester, which was prepared by methylation of 2,3-dihydro-1H-indene-2-carboxylic acid in the presence of sulphuric acid. The 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester was reacted with N-isopropylcyclohexylamide and ethylbromide yielding 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid, then thionyl chloride was added and 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride was obtained. In the next step ethoxymagnesiummalonic acid ethyl ester in dry ether was added to 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride and reaction mixture was treated with sulphuric acid, and 1-(2,3-dihydro-2-ethyl-1H-inden-2-yl)ethanone was obtained, then the intermediate was stirred in methylene chloride and bromine was added by giving a new intermediate 2-bromo-1-(2,3-dihydro-2-methyl-1H-inden-2-yl)ethanone, to which was thereafter added formamide and hydrochloric acid yielding crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. The last step involved hydrogenation of the crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole with 10% palladium on carbon.
EP 0247764 B (ORION-YHTYMÄ OY) Feb. 12, 1987 disclosed the following process for preparation of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride. The process starts by reaction of alpha, alpha′-dibromo-o-xylene with 4-penten-2-one to obtain 1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)ethanone. The obtained intermediate was brominated, e.g. with bromine, methylene chloride was used as solvent and 2-bromo-1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)-ethanone was obtained, which is thereafter reacted with formamide in excess formamide to give a 4(5)-(2,3-dihydro-2-vinyl-1H-inden-2-ylimidazole hydrochloride. As the last step the vinyl group was catalytically hydrogenated to an ethyl group so as to form a product 4(5)-(2,3-dihydro-2-ethyl-1H-inden-2-yl) imidazole.
Another synthetic route for obtaining 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole is disclosed in WAI, Wonf, et al. A Concise Synthesis of Atipamezole. Synthesis. 1995, no. 2, p. 139-140. The cyclization of alpha, alpha′-dibromo-o-xylene with acetylacetone by means of NaOH and tetrabutylammonium bromide in toluene/water at 80° C. under phase-transfer conditions gives the unstable diacetyl derivative, which presumably undergoes cleavage to afford 2-acetylindane. The alkylation of 2-acetylindane with ethyl iodide and potassium tert-butoxide yields 2-acetyl-2-ethylindan, which is brominated with Br2 to give 2-bromoacetyl-2-ethylindan. Finally, this compound is cyclised with formamide at 160° C. (some 2-ethyl-2-(4-oxazolyl)indane is also formed but easily eliminated); the cyclization can also be carried out with formamidine in liquid ammonia.
Although the substitution of formamide by formamidine acetate eliminates the oxazole formation, it does not increase the yield of Atipamezole (<30%) WAI, Wonf, et al. A Concise Synthesis of Atipamezole. Synthesis. 1995, no. 2, p. 139-140 in the final step.